|The immunomodulatory effect of plant lectins: a review with emphasis on ArtinM properties.|
|Jump to Full Text|
|PMID: 23299509 Owner: NLM Status: Publisher|
|Advances in the glycobiology and immunology fields have provided many insights into the role of carbohydrate-protein interactions in the immune system. We aim to present a comprehensive review of the effects that some plant lectins exert as immunomodulatory agents, showing that they are able to positively modify the immune response to certain pathological conditions, such as cancer and infections. The present review comprises four main themes: (1) an overview of plant lectins that exert immunomodulatory effects and the mechanisms accounting for these activities; (2) general characteristics of the immunomodulatory lectin ArtinM from the seeds of Artocarpus heterophyllus; (3) activation of innate immunity cells by ArtinM and consequent induction of Th1 immunity; (4) resistance conferred by ArtinM administration in infections with intracellular pathogens, such as Leishmania (Leishmania) major, Leishmania (Leishmania) amazonensis, and Paracoccidioides brasiliensis. We believe that this review will be a valuable resource for more studies in this relatively neglected area of research, which has the potential to reveal carbohydrate targets for novel prophylactic and therapeutic strategies.|
|Maria A Souza; Fernanda C Carvalho; Luciana P Ruas; Rafael Ricci-Azevedo; Maria Cristina Roque-Barreira|
Related Documents :
|23446149 - Tlr2 deletion promotes arthritis through reduction of il-10.
22990499 - The lnk adaptor protein: a key regulator of normal and pathological hematopoiesis.
22942239 - Interleukin 13 and its role in gut defence and inflammation.
23314569 - The role of candida albicans ap-1 protein against host derived ros in in vivo models of...
22977469 - Suppressive action of resolvin d1 on the production and release of septic mediators in ...
24490899 - The role of innate and lymphoid il-22-producing cells in the immunopathology of primary...
21387369 - Gut, bugs, and brain: role of commensal bacteria in the control of central nervous syst...
9757589 - Uv light affects cell membrane and cytoplasmic targets.
19088199 - Socs3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (ido) and antagoniz...
|Type: JOURNAL ARTICLE Date: 2013-1-9|
|Title: Glycoconjugate journal Volume: - ISSN: 1573-4986 ISO Abbreviation: Glycoconj. J. Publication Date: 2013 Jan|
|Created Date: 2013-1-9 Completed Date: - Revised Date: -|
Medline Journal Info:
|Nlm Unique ID: 8603310 Medline TA: Glycoconj J Country: -|
|Languages: ENG Pagination: - Citation Subset: -|
|Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil.|
|APA/MLA Format Download EndNote Download BibTex|
Journal ID (nlm-ta): Glycoconj J
Journal ID (iso-abbrev): Glycoconj. J
Publisher: Springer US, Boston
© The Author(s) 2013
Received Day: 30 Month: 10 Year: 2012
Revision Received Day: 6 Month: 12 Year: 2012
Accepted Day: 9 Month: 12 Year: 2012
Electronic publication date: Day: 9 Month: 1 Year: 2013
pmc-release publication date: Day: 9 Month: 1 Year: 2013
Print publication date: Year: 2013
Volume: 30First Page: 641 Last Page: 657
PubMed Id: 23299509
Publisher Id: 9464
|The immunomodulatory effect of plant lectins: a review with emphasis on ArtinM properties|
|Maria A. SouzaAff1|
|Fernanda C. CarvalhoAff2|
|Luciana P. RuasAff2|
|Maria Cristina Roque-BarreiraAff2||
Address: +55-16-36020457 +55-16-36020218 email@example.com
Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG Brazil
Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14049900 Ribeirão Preto, São Paulo Brazil
Lectins are carbohydrate-binding proteins of non-immune origin. They are involved in various biological processes, including cell–cell recognition, cell proliferation, cell migration, cell adhesion to the extracellular matrix, and host-parasite interactions [1, 2]. Since the 1960s, plant lectins have been extensively used as valuable tools in biomedical research, because of their interactions with receptor-linked glycans on cell surfaces may trigger cell signaling and biochemical responses.
Several plant lectins exert immunomodulatory activities that are initiated by their interaction with glycan’s moieties present over the surface of immune cells. Such interaction may trigger signal transduction, to produce certain cytokines (Table 1) and induce efficient immune responses against tumors or microbial infections. Hence, immunomodulatory lectins have potential pharmaceutical applications or may help to identify sugar targets for new therapeutic strategies.
The European mistletoe (Viscum album) contains the most noticeable plant lectin endowed with immunomodulatory and antitumor activities. Mistletoe lectins (ML) type I, II and III are a group of glycosylated, 56–64 kDa cytotoxic proteins, which consist of two non-covalently associated pairs of disulfide-linked A-B dimers and are considered to be type-2 ribosome-inactivating protein (RIP). The B-chain selectively binds to β-galactosides , whereas the A-chain catalyzes hydrolysis of the N-glycosydic bond at adenine-4324 in the eukaryotic 28S ribosomal RNA, thereby inhibiting the elongation step of protein biosynthesis . ML-I was identified as the active component of the Viscum album extract and is applied as a complementary treatment of cancer patients . The ML-I B-chain binds to glycans on the surface of cancer cells and allows A-chain entry into the cytoplasm, where the latter chain is enzymatically active and highly cytotoxic. In vitro and in vivo studies have shown that the antitumor effects of ML-I are not only cytotoxic, but also immunomodulatory , an activity that is fundamental to its antitumor properties  (reviewed by Bocci, 1993 ). The cloning of the mistletoe lectin gene and the separate heterologous expression of the single chains [9, 10] have pointed out that the B-chain is responsible for the immunostimulatory activity of ML-I, mainly manifested by augmented IL-12 production and increased cytokine-induced Natural Killer Cells activation . Comparison of the biological activities of the recombinant Mistletoe lectins (rML) -heterodimer  with those of some ML-I mutants  revealed a close correlation between cytotoxicity, apoptosis, and the enzymatic activity of the rML A-chain. Both the enzymatic activity exerted by the A-chain and the carbohydrate binding activity elicited by the B-chain are essential for the ML-I effect as an anticancer agent. The first step in the biological action of ML is to recognize and bind to specific ligands on the surface of target cells. Determination of the sugar specificity of ML has shown that this lectin preferentially binds to β-galactosides in the oligosaccharides of glycoproteins [6, 13, 14]. ML-I has a broad range of affinity for Galα- and Galβ-linked sequences, revealing primary recognition of the terminal galactose unit irrespective of the anomeric linkage [15, 16]. Recent studies on the binding specificity of ML-I toward glycosphingolipids and gangliosides have demonstrated its preferential binding to terminally α2-6-sialylated neolacto-series gangliosides isolated from human granulocytes, whereas rML only marginally binds to neutral gangliosides with terminal galactose moiety. Therefore, ML-I is a type-2 RIP, specific to sialic acid rather than galactose . Indeed, gangliosides and glycoproteins with terminal Neu5Acα2-6Galβ1-4GlcNAc residues are the true and physiologically relevant targets of ML-I recognition on the cell surface . CD 75 s has glycans with terminal α2-6-sialyl-lactosamine and is an important target for rML recognition. It is expressed predominantly on activated B-cell, T-cell, and immature dendritic cells, and it is upregulated in hematological cancers along with the cells of solid tumors. As CD75s is overexpressed in solid tumors, these tumors have been the focus of preclinical trials for the efficacy of rML administration. More than 30 % of the patients were observed to have stabilization in tumor progression associated with increased plasma levels of IL-1β and IFN-γ in response to rML administration. The high IFN-γ response indicates that rML administration stimulates Th1 cells, which may mediate an antitumor T-cell response (reviewed by Zwierzina et al. ).
Besides the European mistletoe, extracts of the Korean and Chinese mistletoes (Viscum album coloratum and Viscum articulatum, respectively) contain type-2 RIPs that bind D-galactose [20, 21] and have high structural homology with ML. Like ML-I, they are endowed with immunomodulatory properties, as demonstrated by in vitro and in vivo studies. The B-chain of the Korean mistletoe lectin (KML) accounts for its immunomodulatory and antitumor activities. This is because the KML B-chain promotes NK cells activation and production of cytokines and inflammatory mediators by macrophages [22, 23]. KML interaction with TLR-4 molecules is responsible for macrophage activation and cytokine production. Macrophages stimulation with KLM results in upregulation of TLR4 expression and enhanced TNF-α production, which is reduced by anti-TLR4 specific antibodies or by assaying macrophages from TLR-4 deficient mice . The recombinant B-chain of the Chinese mistletoe lectin (articulatin) stimulates human mononuclear cells to release TNF-α and IL-6 . This suggests that the B-chain acts as an immunomodulator, like that of the European and Korean mistletoes.
Th1 immunity is induced by immunomodulatory plant lectins. As a rule, the Th1 immune response, manifested by high levels of IFN-γ production, occurs through an IL-12-dependent mechanism. In vitro assays with 12 different plant lectins have shown that six of the lectins induce murine spleen cells to produce IL-12 and IFN-γ: Con A from Canavalia ensiformis, which binds to α-linked mannose; PHA-E and PHA-L from Phaseolus vulgaris, which respectively bind to bisected bi- and tri-antennary complex N-glycans and highly branched non-bisected complex N-glycans); PSA from Pisum sativum, which binds to N-glycans containing α-linked mannose with an α-fucose residue linked to N-acetylchitobiose; and WGA from Triticum vulgaris, which binds to neuraminic acid and glycans containing terminal GlcNAc or GlcNAcβ1-4GlucNAc . Th1 cytokines production is induced by plant lectins such as ArtinM from Artocarpus heterophyllus , the Korean mistletoe lectin from Viscum album coloratum , Cramoll from Cratylia mollis , BanLec from Musa paradisiaca , and garlic lectin from Alium sativum . Some of these lectins are able to induce Th1 cytokines upon interaction with glycosylated receptors on macrophages and/or dendritic cells, such as type 2 and 4 Toll-like receptors (TLR2 and TLR4), respectively recognized by ArtinM  and KML . Several plant lectins may act as TLR agonists . The soybean (SBA), peanut agglutinin (PNA), ConA, and PHA lectins (PHA-L and PHA-P) stimulate extracellular TLRs (2/6, 4, and 5), whereas WGA is pan-active.
Plant lectins can also regulate Th2 immunity. For example, mice receiving ScLL, a lectin from Synadenium carinatum with affinity for β-galactoside-containing glycans, exhibited lower leukocyte trafficking and Th2 cytokine production . ScLL also reduced the pathological sequelae associated with the chronic inflammatory disease asthma in experimental animal models . Th2 immunity can be induced by the lectin B-chain of type-2 RIP from Ricinus communis, which binds to D-galactose containing glycans, including many glycoproteins expressed on the surface of enterocytes. This property motivated the genetic linking of the ricin B-chain with the coding region of the proinsulin gene, expressed as a fusion protein in E. coli  or in Solanum tuberosum (potato plant) . Oral administration of this recombinant fusion protein to prediabetic NOD mice suppressed the auto-immune insulitis, associated with the Th2 immune response, whereas administration of insulin only did not interfere in the course of the disease . The lectin interaction with glycans on the surface of enterocytes favors systemic tolerance to the fused autoantigen. Fusion proteins (immunomodulatory lectin/autoantigen) expressed in the tissues of edible plants provide a conceivable strategy to stimulate Th2 immunity and suppress autoimmunity.
Still regarding mucosal immunity, plant lectins that recognize glycans on the surface of M cells may favor mucosal immunity against orally administered antigens (reviewed by Azizi and cols. 2010 ). M cells express a particular glycosylation pattern on their surface, including L-fucose-containing glycans , and transport a broad range of materials such as particulate antigens from the intestinal lumen to the underlying lymphoid tissue of the mucosae, where local and systemic potent immune response will be initiated. Ulex europaeus agglutinin (UEA-1) recognizes α-L-fucose and selectively binds to the surface of murine M cells. This property explains why UEA-1 is the most studied lectin when enhanced potency of oral or nasal particulate vaccines is the ultimate target. UEA-1-poly-L-lysine coated on the surface of microparticles encoding HIV-1 genes was able to bind to the apical surface of M cells of mice immunized with these particles . Both mucosal and systemic antibody (IgA and IgG) and envelope-specific CTLs responses were augmented in mice immunized with poly-L-lysine conjugated to UEA1 and complexed to a plasmid encoding the HIV-1 envelope . Oral immunization of mice with killed whole Helicobacter pylori or Campylobacter jejuni conjugated to UEA-1 induced protective responses against live challenge . In a recent in vitro study, the hepatitis B surface antigen (HBsAg) encapsulated in liposomes coupled with UEA-1 predominantly targeted M-cells, in a sugar-dependent manner. In addition, the lectinized liposomes induced high sIgA level in mucosal secretions as well as high splenic levels of the IL-2 and IFN-γ cytokines in orally immunized mice .
This overview provides basic information on plant lectins that act as immunomodulators. Although the text is not exhaustive, it shows that studies have mostly focused on the effects that these lectins may exert on cancer. On the other hand, our laboratory has extensively investigated the effects that a plant lectin, named ArtinM, may have on the course of experimental infections. This subject will be detailed in the subsequent sections of this review.
Immunomodulatory lectins may play critical roles in the response against infections. The immunobiological importance of carbohydrate recognition is patent in the literature. However, the role exerted by this kind of interaction in infectious diseases is much less appreciated than in other pathological circumstances, like cancer. One reason for the predominant investment in the study of protein-carbohydrate interactions in cancer is related to the logical impact of Hakomori’s work, where the aberrant glycosylation pattern has been demonstrated in cancer cells thereby enhancing the biological significance of lectins . This author described the aberrant glycosylation of cancer cells, rendering this subject the favourite for studies on the biological roles of lectins. The most relevant publications on this subject have already been approached in the first section of this review. A second reason for the focus on cancer may be the lack of detailed information on biologically relevant assays to understand the role of carbohydrate-lectin interactions in the immune system during infections.
Our research group is interested in the biological repercussions of carbohydrate recognition by animal [43, 44], pathogen [45–47], and plant lectins [48, 49], with particular emphasis on plant lectins extracted from Artocarpus heterophyllus (jackfruit) seeds. Our first study in this field involved Jacalin. This Gal/GalNAc-binding lectin is able to selectively bind to human IgA1 through recognition of the O-glycan core, which is repeatedly found in the hinge region of the α1 heavy chain [50, 51].
The structural characterization of Jacalin raised a new key in lectin classification. The Jacalin-Related Lectins (JRL) were initially featured as having a β-barrel three-dimensional structure. The JRL were subsequently identified to be having two subfamilies of lectins, namely the Gal-specific JRLs and the Man-specific JRLs. Gal-specific homologs of Jacalin exist in the seeds of Artocarpus species  and Osage orange (Maclura pomifera) . Man-specific JRLs have been isolated from species belonging to a wide range of taxonomic groups, including hedge bindweed (Calystegia sepium, family Convolvulaceae) [53, 54], Jerusalem artichoke (Helianthus tuberosus, family Asteraceae) , jackfruit (Artocarpus heterophyllus, family Moraceae) , rice (Oryza sativa, family Gramineae) , banana (Musa acuminata, family Musaceae) , Japanese chestnut (Castanea crenata, family Fagaceae) , faveira (Parkia platycephala, family Fabaceae) , and oilseed rape (Brassica napus, Brassicacea) . Concomitant occurrence of Gal- and Man-specific JLRs has been reported for two plant species only. One is the bark of the black mulberry tree (Morus nigra), which accumulates high concentrations of a Gal-specific JRL (called MornigaG) and a Man-specific homolog (called MornigaM) . The other Artocarpus heterophyllus, seeds of which contain Jacalin, that binds D-galactose and ArtinM that binds to D-mannose. In this review, we will focus on ArtinM.
ArtinM, also known as Artocarpin or KM+ , specifically recognizes the trisaccharide Manα1-3 [Manα1-6] Man core of N-glycans. Interaction of ArtinM with some N-glycans on the cell surface activates innate-immunity cells, such as neutrophils, mast cells, dendritic cells, and macrophages. In this way, ArtinM administration protects against experimental infection with Leishmania spp and Paracoccidioides brasiliensis. The resistance conferred by ArtinM is attributed to recognition of N-glycans in the ectodomain of Toll-like receptors (TLR) expressed on the surface of innate-immunity cells, and the consequent induction of interleukin 12 (IL-12) production and development of the Th1 adaptive immune response (Table 2).
Here, we review the immunomodulatory effect of ArtinM and the mechanisms behind it. We describe murine experimental models of infection and detail its potential therapeutic applications against certain intracellular pathogens.
ArtinM is a homotetramer consisting of 13-kDa subunits. The primary structure of ArtinM comprises a polypeptide chain of 149 amino acids that shares 52 % identity with the Jacalin sequence . The differences between Jacalin and ArtinM are attributed to the absence of internal post-translational cleavage in ArtinM, which preserves a short glycine-rich linker sequence holding the regions analogous to the Jacalin α- and β-chains together . These noncovalently associated Jacalin chains are constituted of 133 and 20 residues, respectively , which derive from a 17 kDa precursor , whose cleavage does not occur in ArtinM molecule.
The three-dimensional structure of each monomer corresponds to a β-barrel, with a β-prism folding (Fig. 1). Each unit has a carbohydrate-recognition domain (CRD) that binds to D-mannose. ArtinM is thus a tetramer with four CRDs . The structure of ArtinM complexes showed that CRD contains the ligand mannotriose. So, the lectin possesses a deep-seated binding site formed by three peptide loops (residues 14–17, 137–141, and 88–95). This binding site comprises two subsets, the primary and secondary sites. Interactions at the primary site, corresponding to two of the loops (residues 14–17 and 137–141), involves hydrogen bonds mainly. The secondary site is composed by the third loop (residues 88–95) and establishes interactions that are primarily van der Waals’ in nature. Mannotriose interacts through the three mannopyranosyl residues in its complex with the lectin; mannopentose interacts with the protein via at least three of the five mannose residues. The complexes provide a structural explanation for the carbohydrate specificities of ArtinM. A detailed comparison with the sugar complexes of Heltuba lectin, another mannose-specific JRL with known three-dimensional structure in the sugar-bound form, has established that the sugar-binding loop constituting the secondary site has a role in the different specificities observed at the oligosaccharide level. This loop is four residues longer in the ArtinM CRD than in the Heltuba CRD, so variation in the loop length is a strategy to generate carbohydrate specificity .
Molecular modeling and crystallization studies have shown that structural differences account for the distinct carbohydrate-binding specificities between ArtinM and Jacalin [63, 66, 67], especially with respect to the recognition of D-mannose, but not D-galactose, by ArtinM. The binding affinity of ArtinM for the glycoprotein horseradish peroxidase (HRP) is 1633-fold higher than that for the monosaccharide D-mannose. This is because ArtinM interacts with the trimannoside core of the HRP N-glycan, which is reinforced by binding to the mannosyl end of the branched oligosaccharide. The superposition of the mannosyl end with the trisaccharide in the complex leads to severe steric clashes involving the xylose residue and loops 86–95 of the lectin. This results in eight hydrogen bonds and increased binding energy .
Although xylose appears to be responsible for the increase in binding energy, it adorns plant N-glycans, as mentioned for HRP, but not mammalian N-glycans . The saccharides that can be coupled to the core of mammalian N-glycans are GlcNAc or Fuc and both are able to establish many van der Waals contacts with loop residues 87–93 of ArtinM . Glycoarray analysis of ArtinM specificity (unpublished data) revealed that subsets of complex-type bi-antennary N-glycans containing Manα1-3(Manα1-6)Manβ1-4GlcNAcβ1-4GlcNAcβ are well recognized by the lectin. The branch attached to Manα1-6 contributes to ArtinM recognition, whereas Manα1-3 elongation reduces lectin binding. A previous study of ArtinM specificity evidenced enhanced recognition of α1-6Man-extended compared with α1-3Man-extended mono-antennary glycans . This unusual binding mechanism accounts for the selectivity of ArtinM binding to certain N-glycans, such as those linked to some protein cell receptors.
ArtinM has potential pharmaceutical applications. However, evaluation of these uses has been limited by the lectin paucity in the extract of A. heterophyllus seeds (less than 0.5 % of the total protein content) . To further explore the properties of ArtinM, its cDNA has been cloned and heterologously expressed in Saccharomyces cerevisiae and Escherichia coli .
Glycoarray analysis of ArtinM has shown that the native (ArtinM) and recombinant (rArtinM) forms display the same specificity for Manα1-3(Manα1-6)Manβ1-4 in the context of N-Glycans. Electrogravimetric analysis, allied to a simple kinetic model for HRP binding to the native and recombinant forms of ArtinM, established equivalence for the kinetics of binding/association affinity of the ligand sites . Therefore, ArtinM CRD is preserved in rArtinM, thus facilitating study of its biological properties.
rArtinM reproduces the biological properties of ArtinM, including neutrophil chemotaxis and mast cell degranulation (unpublished data). IL-12 production also occurs when murine macrophages  are treated with native or recombinant forms of ArtinM. In addition, the recombinant form is able to induce the release of other inflammatory products, such as TNF-α and NO, at the same level as the native form (unpublished data). Besides the in vitro analysis, the ArtinM immunomodulatory effect was reproduced by rArtinM in an assay involving a model of systemic fungal disease caused by Paracoccidioides brasiliensis. Administration of ArtinM or rArtinM to mice before or after fungal inoculation induced Th1 immunity, as attested by high TNF-α and IL-12 levels as well as low IL-4 concentrations. Compared with untreated controls, ArtinM- or rArtinM-treated animals exhibited minor pulmonary lesions and fungal burden .
Box 1. TLR agonist
The first indication that ArtinM has an immunomodulatory property was its ability to induce IL-12 production by murine macrophages. This ability depends on the lectin concentration and CRD, and IL-12 production is selectively inhibited by D-mannose .
IL-12, a 70-kDa heterodimeric cytokine, is important for the activation of the type-1 immune response. A bioactive IL-12p70 form comprises two disulfide-linked subunits: a heavy 40-kDa chain (p40) and a light 35-kDa chain (p35). Macrophages and dendritic cells are the major producers of this cytokine, which is released as a biologically inactive (IL-12p40) and also as a biologically active form (IL-12p70) . IL-12 acts on T lymphocytes and natural killer (NK) cells, and it induces IFN-γ production (Figs. 2 and 5). This hallmark Th1 cytokine functions on T cell proliferation and enhances the cytotoxic activity of macrophages.
By inducing IL-12 production, ArtinM promotes a protective Th1-type response against intracellular pathogens [26, 74, 75]. Reversion of its beneficial effect on IL-12 genetically deficient mice demonstrated the crucial role of IL-12 in the resistance conferred by ArtinM . IL-12 production by phagocytes is generally initiated by interaction of cell-surface TLR with pathogen-associated molecular patterns (PAMPs).
Toll-like receptors play a key part in the initiation of innate immune responses against pathogens in mammals. Moreover, they recognize a variety of PAMPs from bacteria, viruses, and fungi . To date, more than a dozen different TLRs have been identified. TLRs 1–9 are conserved in humans and mice, TLR10 is selectively expressed in humans, and TLR11 is functional in mice . TLRs are type-I transmembrane proteins. Their ectodomains contain leucine-rich repeats that mediate PAMP recognition. Downstream signal transduction requires their intracellular Toll–IL-1 receptor (TIR) domains. Studies on mice deficient in different TLRs have demonstrated that each TLR has a distinct function in terms of PAMP recognition and immune-response induction . This finding opens new frontiers in the development of therapeutic strategies, as attested by the use of a TLR agonist (Box 1).
Amino acid sequencing analysis of all of the TLRs identified to date has revealed the presence of potential N-linked glycosylation sites. Several lines of evidence indicate that oligosaccharides attached to TLRs play important roles in PAMP recognition and in the formation of a functional receptor complex on the cell surface [79–83]. The ectodomain of human TLR2 contains N-glycans linked to residues Asn114, Asn199, Asn414, and Asn442; the glycan at Asn442 contributes to efficient secretion of the TLR2 ectodomain  and PAMP recognition .
We have established that ArtinM-induced IL-12 production occurs via recognition of TLR2 N-glycans (unpublished data) (Fig. 2), but not TLR4 N-glycans; only macrophages from TLR2-deficient mice failed to produce IL-12 in response to ArtinM stimulus . Notably, the ability of ArtinM to induce IL-12 production in wild type (WT) cells was selectively blocked by D-mannose. A gene report assay using TLR2-transfected cells demonstrated direct interaction of ArtinM with TLR2 (unpublished data). The fact that the TLR2 ectodomain contains 4 N-glycans further evidenced TLR2 targeting by ArtinM. We are currently working to identify which glycan(s) is (are) targeted by ArtinM using TLR2 mutants for the ectodomain glycosylation sites (generated in Dr. Nicholas Gay’s laboratory—Department of Biochemistry, University of Cambridge).
The TLR signaling triggered by PAMP recognition frequently involves the adaptor molecule and the myeloid differentiation primary response gene MyD88, and this signaling induces nuclear factor-κB-dependent cytokine production [85, 86]. The signaling triggered by interaction of TLR2 glycans with ArtinM, which accounts for IL-12 induction (Figs. 2 and 5), also requires the MyD88 adaptor molecule . Indeed, macrophages from animals deficient in MyD88 failed to produce IL-12 under ArtinM stimulation. Detection of luciferase activity following ArtinM stimulation confirmed NF-κB activation in a gene report assay using HEK293 cells transfected with TLR2 and NF-κB luciferase (manuscript in preparation).
ArtinM also stimulates dendritic cells to produce IL-12 via TLR2 recognition (unpublished data). Indeed, ArtinM induces maturation of bone marrow-derived dendritic cells (BMDC), as manifested by a higher expression of MHC class II, CD80, and CD86 molecules, which characterizes a profile of mature DCs, capable of priming T cells (Table 2).
Leishmaniasis is a complex of diseases caused by protozoan parasites of the genus Leishmania, with high impact on public health in many regions worldwide. Leishmania multiplies within mononuclear phagocytic system cells. Depending upon the parasite species and host immune response, the infection causes a wide spectrum of clinical manifestations, including self-healing single-skin, mucosal, and diffuse cutaneous lesions. The disease also manifests as a severe systemic infection called visceral leishmaniasis, with liver and spleen enlargement, cachexia, and persistent fever (reviewed by Brodskyn et al. ). The clinical signs have been attributed to the ability of the parasite to spread to lymphatic and hematogenic pathways [88, 89]. Parasite persistence in the tissues accounts for the damage .
Severity of non-healing cutaneous lesions, persistence of parasites at the inoculation site, and scattering by organs such as the liver and spleen  constitute signs of susceptibility to leishmaniasis, which is associated with the immune-response profile the host develops. This relationship has been extensively investigated in murine models of leishmaniasis, which showed different degrees of susceptibility depending on the infected mouse strain. In this context, BALB/c mice are susceptible to L. major infection, while C57BL/6 mice are resistant and able to mount an effective immune response against the parasite . Infection of susceptible BALB/c mice by L. major is an established leishmaniasis model and has contributed to characterization of the dichotomy of the T helper 1 (Th1) and T helper 2 (Th2) profile responses [93, 94], showing that resistance and susceptibility are caused by the appearance of parasite-specific CD4+ Th1 or CD4+ Th2 cells, respectively. Infected BALB/c mice display strong IL-4 and IL-10 mRNA expression and very low IFN-γ mRNA expression, whereas infected C57BL/6 animals exhibit high IFN-γ and IL-10 mRNA levels . Thus, during the early stages of infection, resistance is associated with IFN-γ production, whereas susceptibility is linked to IL-4 production .
We have demonstrated that ArtinM administration elicits IFN-γ secretion by murine spleen cells. We have taken advantage of the well-established model of susceptibility of BALB/c mice to L. major infection and determined whether the IL-12 production induced by ArtinM could reverse the Th2 response that is itself responsible for severe manifestations of the infection. Compared with untreated mice, mice pre-treated with ArtinM (3 doses of 0.5 μg) in combination, or not, with soluble L. major antigens (SLA) and challenged with 1 × 106 promastigotes of L. major had smaller lesions (Fig. 3). Association of ArtinM-pretreatment with anti-IL-12 administration blocked the beneficial effect of ArtinM on the foot lesion. This reinforced that ArtinM acts by changing the pattern of cytokine production, as confirmed by the concentration of cytokines produced by the lymph node cells draining the site of parasite inoculation in mice. Cells from SLA-injected animals released high IL-4 and low IFN-γ concentrations. In contrast, cells from animals injected with Artin-M produced lower IL-4 and higher IFN-γ concentrations. Thus, Artin-M stimulates a drive toward Th1 response in vivo, contrary to the IL-4-driven, polarized Th2 cell response found for the model of a non-healing L. major infection in BALB/c mice.
BALB/c mice immunized with 0.5 μg of ArtinM and challenged with L. amazonensis (1 × 106 infective-stage promastigotes) exhibited significant reduction in the number of parasites (48 %), and this decrease was even greater (80 %) when ArtinM was associated with SLA . IFN-γ production significantly increased when splenic cells from BALB/c mice were stimulated with ArtinM in vitro. Hence, ArtinM was able to control L. amazonensis infection, probably by acting upon initial immune response.
The murine models of Leishmania infection provide strong evidence for the immunomodulatory effect of ArtinM toward a Th1 profile. They also indicate the importance of induced IL-12 production for the protection conferred by ArtinM against Leishmania spp, reinforcing the in vitro results described in section “ArtinM targets TLR2 N-glycans to induce IL-12 production”.
Our research on the effect of ArtinM on experimental leishmaniasis motivated us to evaluate how this lectin interferes with the course of other infection for which host resistance depends on the Th1 response. We chose to investigate the experimental model of paracoccidioidomycosis (PCM), which is the most frequent human systemic mycosis in Latin America, and for which a favorable outcome is associated with early and sustained IFN-γ production.
PCM is caused by the dimorphic fungus Paracoccidioides brasiliensis and is characterized by lesions in the lungs, lymph nodes, skin, and mucous membranes (oral, nasal, and gastrointestinal) . Infection occurs after inhalation of airborne conidia produced by the mycelial form of the fungus. In the lungs, at 37 °C, the inhaled forms are transformed into yeasts, which cause pulmonary granulomatous lesions and can disseminate to many organ systems via the bloodstream and/or lymphatic system [98, 99]. Depending on the host-specific immunity and virulence of the infecting agent, the infection results in a wide spectrum of clinical manifestations. These range from a few localized forms to systemic infection of multiple organs and, eventually, severe and even fatal disease .
Although the mechanisms involved in resistance to P. brasiliensis are still poorly understood, there are clinical and experimental evidences that the cell-mediated immune response plays an important role in host defense against PCM [101–103]. The Th1 immune response exerts a singular role in the asymptomatic form of PCM, while a Th2 pattern is associated with the development of severe disease [104–106]. Resistance and susceptibility to fungal infections have been studied in murine models of infection, which simulate the human mycosis. These models have furnished details of the immune response mechanisms involved in PCM. Resistant mice produce early and sustained IFN-γ and IL-2 levels, whereas susceptible mice produce low IFN-γ but significant IL-5 and IL-10 levels [107, 108]. IFN-γ activates TNF-α secretion and fungal replication inhibition by infected macrophages. TNF-α, in turn, is required for macrophage accumulation and granuloma formation in the lungs of P. brasiliensis-infected mice. Infected mice treated with anti-IFN-γ showed exacerbated pulmonary infection and early fungal dissemination . The essential role of these cytokines has been further demonstrated by using mice genetically deficient in either the IFN-γ or TNF-α receptor [109, 110]. The functions of cytokines accounting for macrophage activation have been consistently documented and are necessary for fungal killing [111–113].
To investigate the interference of ArtinM administration in PCM, our group used an experimental model in which 1 × 106 yeast cells of a virulent P. brasiliensis isolate were intravenously inoculated into BALB/c mice. We evaluated infection severity by the intensity of pulmonary fungal burden and lesions, as well as the extension of fungal dissemination. A screening of regimens of ArtinM administration established that an effective therapeutic protocol consisted of a single subcutaneous injection of ArtinM, 10 days after infection, whereas administration of two subcutaneous injections of ArtinM, on day 10 and day 3 before infection, afforded the best prophylaxis. The therapeutic and prophylactic forms of ArtinM administration were associated with an important decrease in the colony-forming units (CFU) recovered from the mice lungs on day 30 after infection. The lungs presented only mild infiltration of mononuclear cells, contrasting with the lungs of untreated mice, which had multiple sites of focal and confluent epithelioid granulomas, with lymphomonocytic halos circumscribing a high number of viable and non-viable yeast cells (Fig. 4). On day 60 post infection, the untreated mice exhibited disseminated infection, as indicated by the confluent epithelioid granulomas in their liver and spleen. In contrast, infected mice administered with prophylactic or therapeutic ArtinM exhibited no granulomas or yeast cells in the pulmonary sections and had a well-preserved bronchoalveolar structure along with expected no fungal dissemination to the liver or spleen. Therefore, ArtinM exerted a beneficial effect on the severity of P. brasiliensis infection [31, 74, 114].
The advantageous effect of ArtinM administration correlates with an adequate milieu of pulmonary mediators. The lung homogenates from mice infected with P. brasiliensis and administered with prophylactic or therapeutic ArtinM showed higher levels of the pro-inflammatory cytokines IL-12 and TNF-α, and also of NO. In addition, lower IL-4 and higher IFN-γ concentrations were stably produced during the disease course in ArtinM-treated mice, whilst high IL-4 and low IFN-γ concentrations were detected in untreated control mice. As in the case of the Leishmania infection model, we concluded that a drive toward a Th1 response is stimulated in vivo by ArtinM. Besides that, we verified stable IL-10 production in the ArtinM-treated mice. Therefore, ArtinM administration correlates with the establishment of Th1 immunity, balanced by the presence of an anti-inflammatory cytokine (Fig. 5). Interestingly, we also observed, but did not report, IL-10 production in the BALB/c mice infected with L. major and administered with ArtinM.
We have investigated the importance of IL-12 for the beneficial effects of ArtinM on experimental PCM. IL-12 knockout (KO) mice inoculated with the fungus and treated with ArtinM were not protected against the infection, showing the crucial nature of IL-12 is for the immunomodulatory effect exerted by ArtinM. We propose that ArtinM interferes with the outcome of P. brasiliensis infection, by modulating the host immunity against the fungus according to the following events: recognition of TLR2 glycans by the lectin; induction of IL-12 production (Fig. 2); generation of a Th1-balanced immunity; and protection against P. brasiliensis.
The parallel utilization of recombinant ArtinM to treat the P. brasiliensis-infected mice provided evidence that the administration of ArtinM or rArtinM has an equally protective effect against the infection. .
In conclusion, ArtinM exerts a protective effect against experimental infection with P. brasiliensis, leading to a Th1-biased immune response with a direct beneficial effect on the severity of lung lesions. The mechanism of protection involves induction of endogenous IL-12, in a process dependent on the MyD88/TLR2 signaling pathway. The detection of IL-10 production in ArtinM-treated animals revealed that the induced Th1-prone immune response is regulated to prevent systemic immune pathology, as indicated by the absence of exacerbated inflammatory lesions in animals administered with ArtinM (Fig. 5). The identification of the cell source of IL-10 is under investigation, as part of a study of ArtinM pleiotropic activities (Box 2) [115, 116].
Box 2. ArtinM exerts positive or negative control of Th17 immunity.
The new perspectives offered by ArtinM in the development of antifungal therapy has been reviewed recently .
Pleiotropism refers to the ability of certain mediators, such as cytokines, to act on different cell types. It is an important property shared by all cytokines, and accounts for their ability to act on innate and also adaptive immunity. Various examples illustrate the pleiotropic activities of cytokines. IL-12 enhances NK cell cytotoxicity in innate immunity and induces Th1 cell differentiation in adaptive immunity. IFN-γ, in turn, activates macrophages in the innate and also in the adaptative cell-mediated immune response. Moreover, it increases expression of MHC molecules and enhances antigen processing and presentation. IL-10 (which is produced by macrophages, some T helper cells, and mast cells) inhibits activated macrophages and dendritic cells, decreases inflammation by inhibiting Th1 cells, and inhibits IL-12 release by macrophages. Although pleiotropism allows cytokines to mediate diverse effects, numerous undesirable side effects limit their therapeutic use. The biological characterization of ArtinM indicates its pleiotropism. As already mentioned, ArtinM activates a variety of cells by interacting with glycosylated receptors on their surface. In addition to the interaction with TLR2 glycans in macrophages and dendritic cells (which is responsible for IL12 production and induction of Th1 immunity), ArtinM activates neutrophils via recognition of N-glycans linked to receptors such as CXCR2 and TLR2. This induces cell migration, release of inflammatory mediators, and enhancement of effector functions. ArtinM also targets glycosylated receptors on the surface of mast cells, which leads to cell degranulation; release of cytokines such as TNF-α, IL-10, and IL-8; and recruitment and differentiation of mast cell precursors from the bone marrow. By analogy with the limitations found for the therapeutic use of cytokines, we are currently evaluating whether the pleiotropic effects of ArtinM impair its immunomodulatory activity. Preliminary results suggest that the pleiotropic effects of ArtinM are not harmful in our models of infection; in fact, neutrophil activation induced by ArtinM appears to favor elimination of intracellular pathogens without causing exacerbated inflammation. We hypothesize that the potential pro-inflammatory effects of ArtinM are counterbalanced by its ability to induce IL-10 production, and we are currently investigating the cell source of this cytokine.
In this review, we have focused on the immunomodulatory properties of ArtinM. We have provided a structural basis of sugar recognition by ArtinM and applied our knowledge of lectin specificity to explain its interaction with glycosylated receptors on the cell surface. We specifically studied the interaction of ArtinM with TLR2 N-glycans on the surface of macrophages and dendritic cells, because this interaction is primarily responsible for the immunomodulatory activity of this lectin. This activity is characterized by induction of IL-12 production, development of Th1 immunity, and ability to confer protection against murine infections with intracellular pathogens, such as Leishmania spp and P. brasiliensis. We compared the immunomodulatory activity of ArtinM with those triggered by TLR agonists and considered the former lectin to be advantageous, because of its pleiotropic feature. The presence of multiple glycan targets of ArtinM on the surface of different cells (including neutrophils, macrophages, dendritic cells, and mast cells) appears to favor efficient immunomodulation. However, many questions remain to be answered. We are currently working on: (i) determining the specificity of ArtinM toward complex glycans; (ii) identifying cell-surface receptors through which N-glycans are recognized by ArtinM; (iii) extending the range of animal models used to assay the effects of ArtinM immunomodulatory activity; (iv) evaluating ArtinM immunomodulatory activity during the early phases of acute infections; and (v) understanding the mechanisms responsible for the ArtinM immunomodulatory activity.
|ArtinM||Artocarpus heterophyllus lectin manose binding|
|rML||Recombinant mistletoe lectin|
|RIPs||Type-2 ribosomes inactivating proteins|
|NK||Natural killer cells|
|IL-12||Interleukin – (12)|
|TNF-α||Tumor necrosis factor-alpha|
|Th1||T helper 1|
|Th2||T helper 2|
|Th17||T helper 17|
|MHC II||Major histocompatibility complex class II|
|KML||Korean mistletoe lectin|
|PHA-E and PHA-L||Phytohaemagglutinin|
|Con A||Concanavalin A|
|PSA||Pisum sativum agglutinin|
|WGA||Wheat germ agglutinin|
|Cramoll||Cratylia mollis lectin|
|BanLec||Lectin from Musa paradisiacal|
|Conbr||Lectin from Canavalia brasiliensis|
|DrosL||Dioclea rostrata lectin|
|DvioL||Dioclea violacea lectin|
|Dvirl||Dioclea virgata lectin|
|Garlic||Lectin from Alium sativum|
|PAA||Pisum arvense agglutinin (lectin from Pisum arvense)|
|PWM||Pokeweed mitogen (lectin from Phytolacca Americana)|
|AAL||Aleuria aurantia lectin|
|ScLL||Synadenium carinatum lectin latex|
|UEA-1||Ulex europaeus agglutinin|
|CTL||Cytotoxic T lymphocytes|
|NOD||Non-obese diabetic mice|
|PAMPs||Pathogen-associated molecular patterns|
|MyD88||Myeloid differentiation primary response gene 88|
We thank Dr Constance Oliver and Dr. Ademilson Panunto Castelo for comments on the manuscript and Dr Els Van Damme for reviewing the final version of the manuscript and supporting its submission as a member of Editorial Board of the Glycoconjugate Journal. Preparation of this manuscript was supported by grants number 2006/60642-2 from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
|1..||Van Damme EJM,Peumans WJ,Barre A,Rougé P. Plant lectins: a composite of several distinct families of structurally and evolutionary related proteins with diverse biological rolesCrit. Rev. Plant Sci.Year: 199817657569210.1080/07352689891304276|
|2..||Van Damme EJM,Lannoo N,Peumans WJ. Plant LectinsAdv. Bot. Res.Year: 20084810720910.1016/S0065-2296(08)00403-5|
|3..||Olsnes S,Stirpe F,Sandvig K,Pihl A. Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe)J. Biol. Chem.Year: 19822572213263132707142144|
|4..||Endo Y,Tsurugi K,Franz H. The site of action of the A-chain of mistletoe lectin I on eukaryotic ribosomes. The RNA N-glycosidase activity of the proteinFEBS Lett.Year: 1988231237838010.1016/0014-5793(88)80853-63360143|
|5..||Klopp R,Schmidt W,Werner E,Werner M,Niemer W,Beuth J. Influence of complementary Viscum album (Iscador) administration on microcirculation and immune system of ear, nose and throat carcinoma patients treated with radiation and chemotherapyAnticancer. Res.Year: 2005251B60161015816634|
|6..||Hajto T,Hostanska K,Gabius HJ. Modulatory potency of the beta-galactoside-specific lectin from mistletoe extract (Iscador) on the host defense system in vivo in rabbits and patientsCancer Res.Year: 19894917480348082758413|
|7..||Beuth J,Ko HL,Gabius HJ,Pulverer G. Influence of treatment with the immunomodulatory effective dose of the beta-galactoside-specific lectin from mistletoe on tumor colonization in BALB/c-mice for two experimental model systemsIn VivoYear: 19915129321932621|
|8..||Bocci V. Mistletoe (viscum album) lectins as cytokine inducers and immunoadjuvant in tumor therapy. A reviewJ. Biol. Regul. Homeost. AgentsYear: 199371168346712|
|9..||Eck J,Langer M,Mockel B,Baur A,Rothe M,Zinke H,Lentzen H. Cloning of the mistletoe lectin gene and characterization of the recombinant A-chainEur. J. Biochem. / FEBSYear: 1999264377578410.1046/j.1432-1327.1999.00638.x|
|10..||Eck J,Langer M,Mockel B,Witthohn K,Zinke H,Lentzen H. Characterization of recombinant and plant-derived mistletoe lectin and their B-chainsEur. J. Biochem. / FEBSYear: 1999265278879710.1046/j.1432-1327.1999.00784.x|
|11..||Hajto T,Hostanska K,Weber K,Zinke H,Fischer J,Mengs U,Lentzen H,Saller R. Effect of a recombinant lectin, Viscum album agglutinin on the secretion of interleukin-12 in cultured human peripheral blood mononuclear cells and on NK-cell-mediated cytotoxicity of rat splenocytes in vitro and in vivoNat. Immun.Year: 1998161344610.1159/0000694289789123|
|12..||Langer M,Mockel B,Eck J,Zinke H,Lentzen H. Site-specific mutagenesis of mistletoe lectin: the role of RIP activity in apoptosisBiochem. Biophys. Res. Commun.Year: 1999264394494810.1006/bbrc.1999.161010544035|
|13..||Barbieri L,Battelli MG,Stirpe F. Ribosome-inactivating proteins from plantsBiochim. Biophys. ActaYear: 199311543–42372828280743|
|14..||Gabius S,Joshi S,Kayser K,Gabius H. The galactoside-specific lectin from mistletoe as biological response modifierInt. J. Oncol.Year: 19921670570821584604|
|15..||Lee RT,Gabius HJ,Lee YC. The sugar-combining area of the galactose-specific toxic lectin of mistletoe extends beyond the terminal sugar residue: comparison with a homologous toxic lectin, ricinCarbohydr. Res.Year: 199425426927610.1016/0008-6215(94)84259-08180989|
|16..||Gupta D,Kaltner H,Dong X,Gabius HJ,Brewer CF. Comparative cross-linking activities of lactose-specific plant and animal lectins and a natural lactose-binding immunoglobulin G fraction from human serum with asialofetuinGlycobiologyYear: 19966884384910.1093/glycob/6.8.8439023547|
|17..||Muthing J,Burg M,Mockel B,Langer M,Metelmann-Strupat W,Werner A,Neumann U,Peter-Katalinic J,Eck J. Preferential binding of the anticancer drug rViscumin (recombinant mistletoe lectin) to terminally alpha2-6-sialylated neolacto-series gangliosidesGlycobiologyYear: 200212848549710.1093/glycob/cwf06212145189|
|18..||Muthing J,Meisen I,Bulau P,Langer M,Witthohn K,Lentzen H,Neumann U,Peter-Katalinic J. Mistletoe lectin I is a sialic acid-specific lectin with strict preference to gangliosides and glycoproteins with terminal Neu5Ac alpha 2-6Gal beta 1-4GlcNAc residuesBiochemistryYear: 200443112996300710.1021/bi030189215023051|
|19..||Zwierzina H,Bergmann L,Fiebig H,Aamdal S,Schoffski P,Witthohn K,Lentzen H. The preclinical and clinical activity of aviscumine: a potential anticancer drugEur. J. CancerYear: 201147101450145710.1016/j.ejca.2011.02.02221482461|
|20..||Yoon TJ,Yoo YC,Kang TB,Shimazaki K,Song SK,Lee KH,Kim SH,Park CH,Azuma I,Kim JB. Lectins isolated from Korean mistletoe (Viscum album coloratum) induce apoptosis in tumor cellsCancer Lett.Year: 19991361334010.1016/S0304-3835(98)00300-010211936|
|21..||Lu TL,Chuang JY,Yang JS,Chiu ST,Hsiao NW,Wu MC,Wu SH,Hsu CH. Production of active nonglycosylated recombinant B-chain of type-2 ribosome-inactivating protein from viscum articulatum and its biological effects on peripheral blood mononuclear cellsEvid. Based Complement. Alternat. Med.Year: 2011201128374721584270|
|22..||Yoon TJ,Yoo YC,Kang TB,Song SK,Lee KB,Her E,Song KS,Kim JB. Antitumor activity of the Korean mistletoe lectin is attributed to activation of macrophages and NK cellsArch. Pharm. Res.Year: 2003261086186710.1007/BF0298003314609136|
|23..||Kang TB,Yoo YC,Lee KH,Yoon HS,Her E,Kim JB,Song SK. Korean mistletoe lectin (KML-IIU) and its subchains induce nitric oxide (NO) production in murine macrophage cellsJ. Biomed. Sci.Year: 200815219720410.1007/s11373-007-9210-217940853|
|24..||Park HJ,Hong JH,Kwon HJ,Kim Y,Lee KH,Kim JB,Song SK. TLR4-mediated activation of mouse macrophages by Korean mistletoe lectin-C (KML-C)Biochem. Biophys. Res. Commun.Year: 2010396372172510.1016/j.bbrc.2010.04.16920450885|
|25..||Muraille E,Pajak B,Urbain J,Leo O. Carbohydrate-bearing cell surface receptors involved in innate immunity: interleukin-12 induction by mitogenic and nonmitogenic lectinsCell. Immunol.Year: 199919111910.1006/cimm.1998.14019918681|
|26..||Panunto-Castelo A,Souza MA,Roque-Barreira MC,Silva JS. KM(+), a lectin from Artocarpus integrifolia, induces IL-12 p40 production by macrophages and switches from type 2 to type 1 cell-mediated immunity against Leishmania major antigens, resulting in BALB/c mice resistance to infectionGlycobiologyYear: 200111121035104210.1093/glycob/11.12.103511805076|
|27..||Yoon TJ,Yoo YC,Kang TB,Her E,Kim SH,Kim K,Azuma I,Kim JB. Cellular and humoral adjuvant activity of lectins isolated from Korean mistletoe (Viscum album colaratum)Int. Immunopharmacol.Year: 20011588188910.1016/S1567-5769(01)00024-811379043|
|28..||de Melo CM,de Castro MC,de Oliveira AP,Gomes FO,Pereira VR,Correia MT,Coelho LC,Paiva PM. Immunomodulatory response of Cramoll 1,4 lectin on experimental lymphocytesPhytother. Res.Year: 201024111631163610.1002/ptr.315621031620|
|29..||Stojanovic MM,Zivkovic IP,Petrusic VZ,Kosec DJ,Dimitrijevic RD,Jankov RM,Dimitrijevic LA,Gavrovic-Jankulovic MD. In vitro stimulation of Balb/c and C57 BL/6 splenocytes by a recombinantly produced banana lectin isoform results in both a proliferation of T cells and an increased secretion of interferon-gammaInt. Immunopharmacol.Year: 200910112012910.1016/j.intimp.2009.10.00719874914|
|30..||Dong Q,Sugiura T,Toyohira Y,Yoshida Y,Yanagihara N,Karasaki Y. Stimulation of IFN-gamma production by garlic lectin in mouse spleen cells: involvement of IL-12 via activation of p38 MAPK and ERK in macrophagesPhytomedicineYear: 201118430931610.1016/j.phymed.2010.06.00820724126|
|31..||Coltri KC,Oliveira LL,Ruas LP,Vendruscolo PE,Goldman MH,Panunto-Castelo A,Roque-Barreira MC. Protection against Paracoccidioides brasiliensis infection conferred by the prophylactic administration of native and recombinant ArtinMMed. Mycol.Year: 201048679279910.3109/1369378090350167120392144|
|32..||Unitt J,Hornigold D. Plant lectins are novel Toll-like receptor agonistsBiochem. Pharmacol.Year: 201181111324132810.1016/j.bcp.2011.03.01021420389|
|33..||Rogerio AP,Cardoso CR,Fontanari C,Souza MA,Afonso-Cardoso SR,Silva EV,Koyama NS,Basei FL,Soares EG,Calixto JB,Stowell SR,Dias-Baruffi M,Faccioli LH. Anti-asthmatic potential of a D-galactose-binding lectin from Synadenium carinatum latexGlycobiologyYear: 200717879580410.1093/glycob/cwm05317522108|
|34..||Carter JE 3rd,Yu J,Choi NW,Hough J,Henderson D,He D,Langridge WH. Bacterial and plant enterotoxin B subunit-autoantigen fusion proteins suppress diabetes insulitisMol. Biotechnol.Year: 200632111510.1385/MB:32:1:00116382177|
|35..||Carter JE 3rd,Odumosu O,Langridge WH. Expression of a ricin toxin B subunit: insulin fusion protein in edible plant tissuesMol. Biotechnol.Year: 20104429010010.1007/s12033-009-9217-119898971|
|36..||Azizi A,Kumar A,Diaz-Mitoma F,Mestecky J. Enhancing oral vaccine potency by targeting intestinal M cellsPLoS Pathog.Year: 2010611e100114710.1371/journal.ppat.100114721085599|
|37..||Jang MH,Kweon MN,Iwatani K,Yamamoto M,Terahara K,Sasakawa C,Suzuki T,Nochi T,Yokota Y,Rennert PD,Hiroi T,Tamagawa H,Iijima H,Kunisawa J,Yuki Y,Kiyono H. Intestinal villous M cells: an antigen entry site in the mucosal epitheliumProc. Natl. Acad. Sci. U. S. A.Year: 2004101166110611510.1073/pnas.040096910115071180|
|38..||Manocha M,Pal PC,Chitralekha KT,Thomas BE,Tripathi V,Gupta SD,Paranjape R,Kulkarni S,Rao DN. Enhanced mucosal and systemic immune response with intranasal immunization of mice with HIV peptides entrapped in PLG microparticles in combination with Ulex Europaeus-I lectin as M cell targetVaccineYear: 20052348–495599561710.1016/j.vaccine.2005.06.03116099080|
|39..||Wang X,Kochetkova I,Haddad A,Hoyt T,Hone DM,Pascual DW. Transgene vaccination using Ulex europaeus agglutinin I (UEA-1) for targeted mucosal immunization against HIV-1 envelopeVaccineYear: 200523293836384210.1016/j.vaccine.2005.02.02315893622|
|40..||Chionh YT,Wee JL,Every AL,Ng GZ,Sutton P. M-cell targeting of whole killed bacteria induces protective immunity against gastrointestinal pathogensInfect. Immun.Year: 20097772962297010.1128/IAI.01522-0819380476|
|41..||Gupta PN,Vyas SP. Investigation of lectinized liposomes as M-cell targeted carrier-adjuvant for mucosal immunizationColloids Surf. B: BiointerfacesYear: 201082111812510.1016/j.colsurfb.2010.08.02720843665|
|42..||Hakomori S. Aberrant glycosylation in tumors and tumor-associated carbohydrate antigensAdv. Cancer Res.Year: 19895225733110.1016/S0065-230X(08)60215-82662714|
|43..||Dias-Baruffi M,Cunha FQ,Ferreira SH,Roque-Barreira MC. Macrophage-released neutrophil chemotactic factor (MNCF) induces PMN-neutrophil migration through lectin-like activityAgents ActionsYear: 199338 Spec NoC54C5610.1007/BF019911358317322|
|44..||Bernardes ES,Silva NM,Ruas LP,Mineo JR,Loyola AM,Hsu DK,Liu FT,Chammas R,Roque-Barreira MC. Toxoplasma gondii infection reveals a novel regulatory role for galectin-3 in the interface of innate and adaptive immunityAm. J. Pathol.Year: 200616861910192010.2353/ajpath.2006.05063616723706|
|45..||Coltri KC,Casabona-Fortunato AS,Gennari-Cardoso ML,Pinzan CF,Ruas LP,Mariano VS,Martinez R,Rosa JC,Panunto-Castelo A,Roque-Barreira MC. Paracoccin, a GlcNAc-binding lectin from Paracoccidioides brasiliensis, binds to laminin and induces TNF-alpha production by macrophagesMicrobes Infect.Year: 20068370471310.1016/j.micinf.2005.09.00816476564|
|46..||Lourenco EV,Pereira SR,Faca VM,Coelho-Castelo AA,Mineo JR,Roque-Barreira MC,Greene LJ,Panunto-Castelo A. Toxoplasma gondii micronemal protein MIC1 is a lactose-binding lectinGlycobiologyYear: 200111754154710.1093/glycob/11.7.54111447133|
|47..||Ganiko L,Puccia R,Mariano VS,Sant’Anna OA,Freymuller E,Roque-Barreira MC,Travassos LR. Paracoccin, an N-acetyl-glucosamine-binding lectin of Paracoccidioides brasiliensis, is involved in fungal growthMicrobes InfectYear: 20079669570310.1016/j.micinf.2007.02.01217400504|
|48..||Dias-Baruffi M,Sakamoto M,Rossetto S,Vozari-Hampe MM,Roque-Barreira MC. Neutrophil migration and aggregation induced by euphorbin, a lectin from the latex of Euphorbia milii, var. miliiInflamm. Res.Year: 2000491273273610.1007/s00011005065411211926|
|49..||Santos-de-Oliveira R,Dias-Baruffi M,Thomaz SM,Beltramini LM,Roque-Barreira MC. A neutrophil migration-inducing lectin from Artocarpus integrifoliaJ. Immunol.Year: 19941534179818078046246|
|50..||Roque-Barreira MC,Campos-Neto A. Jacalin: an IgA-binding lectinJ. Immunol.Year: 19851343174017433871459|
|51..||Kondoh H,Kobayashi K,Hagiwara K. A simple procedure for the isolation of human secretory IgA of IgA1 and IgA2 subclass by a jackfruit lectin, jacalin, affinity chromatographyMol. Immunol.Year: 198724111219122210.1016/0161-5890(87)90169-63122030|
|52..||Bausch JN,Poretz RD. Purification and properties of the hemagglutinin from Maclura pomifera seedsBiochemistryYear: 197716265790579410.1021/bi00645a023588553|
|53..||Peumans WJ,Winter HC,Bemer V,Van Leuven F,Goldstein IJ,Truffa-Bachi P,Van Damme EJ. Isolation of a novel plant lectin with an unusual specificity from Calystegia sepiumGlycoconj. J.Year: 199714225926510.1023/A:10185021077079111143|
|54..||Van Damme EJ,Barre A,Verhaert P,Rouge P,Peumans WJ. Molecular cloning of the mitogenic mannose/maltose-specific rhizome lectin from Calystegia sepiumFEBS Lett.Year: 19963972–335235610.1016/S0014-5793(96)01211-28955378|
|55..||Van Damme EJ,Barre A,Mazard AM,Verhaert P,Horman A,Debray H,Rouge P,Peumans WJ. Characterization and molecular cloning of the lectin from Helianthus tuberosusEur. J. Biochem. / FEBSYear: 19992591–213514210.1046/j.1432-1327.1999.00013.x|
|56..||Zhang W,Peumans WJ,Barre A,Astoul CH,Rovira P,Rouge P,Proost P,Truffa-Bachi P,Jalali AA,Van Damme EJ. Isolation and characterization of a jacalin-related mannose-binding lectin from salt-stressed rice (Oryza sativa) plantsPlantaYear: 2000210697097810.1007/s00425005070510872230|
|57..||Peumans WJ,Zhang W,Barre A,Houles Astoul C,Balint-Kurti PJ,Rovira P,Rouge P,May GD,Van Leuven F,Truffa-Bachi P,Van Damme EJ. Fruit-specific lectins from banana and plantainPlantaYear: 2000211454655410.1007/s00425000030711030554|
|58..||Nomura K,Nakamura S,Fujitake M,Nakanishi T. Complete amino acid sequence of Japanese chestnut agglutininBiochem. Biophys. Res. Commun.Year: 20002761232810.1006/bbrc.2000.342011006076|
|59..||Mann K,Farias CM,Del Sol FG,Santos CF,Grangeiro TB,Nagano CS,Cavada BS,Calvete JJ. The amino-acid sequence of the glucose/mannose-specific lectin isolated from Parkia platycephala seeds reveals three tandemly arranged jacalin-related domainsEur. J. Biochem. / FEBSYear: 2001268164414442210.1046/j.1432-1327.2001.02368.x|
|60..||Geshi N,Brandt A. Two jasmonate-inducible myrosinase-binding proteins from Brassica napus L. seedlings with homology to jacalinPlantaYear: 1998204329530410.1007/s0042500502599530873|
|61..||Van Damme EJ,Hause B,Hu J,Barre A,Rouge P,Proost P,Peumans WJ. Two distinct jacalin-related lectins with a different specificity and subcellular location are major vegetative storage proteins in the bark of the black mulberry treePlant Physiol.Year: 2002130275776910.1104/pp.00589212376642|
|62..||Pereira-da-Silva G,Roque-Barreira MC,Van Damme EJ. Artin M: a rational substitution for the names artocarpin and KM+Immunol. Lett.Year: 20081191–211411510.1016/j.imlet.2008.06.00218602950|
|63..||Rosa JC,De Oliveira PS,Garratt R,Beltramini L,Resing K,Roque-Barreira MC,Greene LJ. KM+, a mannose-binding lectin from Artocarpus integrifolia: amino acid sequence, predicted tertiary structure, carbohydrate recognition, and analysis of the beta-prism foldProtein Sci.Year: 199981132410.1110/ps.8.1.1310210179|
|64..||Young NM,Johnston RA,Watson DC. The amino acid sequences of jacalin and the Maclura pomifera agglutininFEBS Lett.Year: 1991282238238410.1016/0014-5793(91)80518-82037053|
|65..||Ngoc LD,Brillard M,Hoebeke J. The alpha- and beta-subunits of the jacalins are cleavage products from a 17-kDa precursorBiochim. Biophys. ActaYear: 19931156221922210.1016/0304-4165(93)90139-Y8427879|
|66..||Jeyaprakash AA,Srivastav A,Surolia A,Vijayan M. Structural basis for the carbohydrate specificities of artocarpin: variation in the length of a loop as a strategy for generating ligand specificityJ. Mol. Biol.Year: 2004338475777010.1016/j.jmb.2004.03.04015099743|
|67..||Pratap JV,Jeyaprakash AA,Rani PG,Sekar K,Surolia A,Vijayan M. Crystal structures of artocarpin, a Moraceae lectin with mannose specificity, and its complex with methyl-alpha-D-mannose: implications to the generation of carbohydrate specificityJ. Mol. Biol.Year: 2002317223724710.1006/jmbi.2001.543211902840|
|68..||Lerouge P,Cabanes-Macheteau M,Rayon C,Fischette-Laine AC,Gomord V,Faye L. N-glycoprotein biosynthesis in plants: recent developments and future trendsPlant Mol. Biol.Year: 1998381–2314810.1023/A:10060120056549738959|
|69..||Nakamura-Tsuruta S,Uchiyama N,Peumans WJ,Van Damme EJ,Totani K,Ito Y,Hirabayashi J. Analysis of the sugar-binding specificity of mannose-binding-type Jacalin-related lectins by frontal affinity chromatography—an approach to functional classificationFEBS J.Year: 200827561227123910.1111/j.1742-4658.2008.06282.x18266762|
|70..||daSilva LL,de Molfetta-Machado JB,Panunto-Castelo A,Denecke J,Goldman GH,Roque-Barreira MC,Goldman MH. cDNA cloning and functional expression of KM+, the mannose-binding lectin from Artocarpus integrifolia seedsBiochim. Biophys. ActaYear: 20051726325126010.1016/j.bbagen.2005.09.00616242845|
|71..||Pesquero NC,Pedroso MM,Watanabe AM,Goldman MH,Faria RC,Roque-Barreira MC,Bueno PR. Real-time monitoring and kinetic parameter estimation of the affinity interaction of jArtinM and rArtinM with peroxidase glycoprotein by the electrogravimetric techniqueBiosens. Bioelectron.Year: 2010261364210.1016/j.bios.2010.04.04720605432|
|72..||Pranchevicius MC,Oliveira LL,Rosa JC,Avanci NC,Quiapim AC,Roque-Barreira MC,Goldman MH. Characterization and optimization of ArtinM lectin expression in Escherichia coliBMC Biotechnol.Year: 2012124410.1186/1472-6750-12-4422857259|
|73..||Trinchieri G,Wysocka M,D’Andrea A,Rengaraju M,Aste-Amezaga M,Kubin M,Valiante NM,Chehimi J. Natural killer cell stimulatory factor (NKSF) or interleukin-12 is a key regulator of immune response and inflammationProg Growth Factor ResYear: 19924435536810.1016/0955-2235(92)90016-B1364096|
|74..||Coltri KC,Oliveira LL,Pinzan CF,Vendruscolo PE,Martinez R,Goldman MH,Panunto-Castelo A,Roque-Barreira MC. Therapeutic administration of KM+ lectin protects mice against Paracoccidioides brasiliensis infection via interleukin-12 production in a toll-like receptor 2-dependent mechanismAm. J. Pathol.Year: 2008173242343210.2353/ajpath.2008.08012618599609|
|75..||Teixeira CR,Cavassani KA,Gomes RB,Teixeira MJ,Roque-Barreira MC,Cavada BS,da Silva JS,Barral A,Barral-Netto M. Potential of KM + lectin in immunization against Leishmania amazonensis infectionVaccineYear: 200624153001300810.1016/j.vaccine.2005.11.06716455170|
|76..||Takeda K,Akira S. Toll receptors and pathogen resistanceCell. Microbiol.Year: 20035314315310.1046/j.1462-5822.2003.00264.x12614458|
|77..||West AP,Koblansky AA,Ghosh S. Recognition and signaling by toll-like receptorsAnnu. Rev. Cell Dev. Biol.Year: 20062240943710.1146/annurev.cellbio.21.122303.11582716822173|
|78..||Akira S,Uematsu S,Takeuchi O. Pathogen recognition and innate immunityCellYear: 2006124478380110.1016/j.cell.2006.02.01516497588|
|79..||Choe J,Kelker MS,Wilson IA. Crystal structure of human toll-like receptor 3 (TLR3) ectodomainScienceYear: 2005309573458158510.1126/science.111525315961631|
|80..||Weber AN,Morse MA,Gay NJ. Four N-linked glycosylation sites in human toll-like receptor 2 cooperate to direct efficient biosynthesis and secretionJ. Biol. Chem.Year: 200427933345893459410.1074/jbc.M40383020015173186|
|81..||da Silva Correia J,Ulevitch RJ. MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptorJ. Biol. Chem.Year: 200227731845185410.1074/jbc.M10991020011706042|
|82..||Ohnishi T,Muroi M,Tanamoto K. MD-2 is necessary for the toll-like receptor 4 protein to undergo glycosylation essential for its translocation to the cell surfaceClin. Diagn. Lab. Immunol.Year: 200310340541012738639|
|83..||Ohnishi T,Muroi M,Tanamoto K. N-linked glycosylations at Asn(26) and Asn(114) of human MD-2 are required for toll-like receptor 4-mediated activation of NF-kappaB by lipopolysaccharideJ. Immunol.Year: 200116763354335911544325|
|84..||Kataoka H,Yasuda M,Iyori M,Kiura K,Narita M,Nakata T,Shibata K. Roles of N-linked glycans in the recognition of microbial lipopeptides and lipoproteins by TLR2Cell. Microbiol.Year: 2006871199120910.1111/j.1462-5822.2006.00702.x16819971|
|85..||Kuka M,Baronio R,Valentini S,Monaci E,Muzzi A,Aprea S,De Gregorio E,D’Oro U. Src kinases are required for a balanced production of IL-12/IL-23 in human dendritic cells activated by Toll-like receptor agonistsPLoS OneYear: 201057e1149110.1371/journal.pone.001149120634889|
|86..||Li F,Thiele I,Jamshidi N,Palsson BO. Identification of potential pathway mediation targets in Toll-like receptor signalingPLoS Comput. Biol.Year: 200952e100029210.1371/journal.pcbi.100029219229310|
|87..||Brodskyn C,de Oliveira CI,Barral A,Barral-Netto M. Vaccines in leishmaniasis: advances in the last five yearsExpert. Rev. VaccinesYear: 20032570571710.1586/14760518.104.22.168514711330|
|88..||Martinez JE,Alba,Arias L,Escobar MA,Saravia NG. Haemoculture of Leishmania (Viannia) braziliensis from two cases of mucosal leishmaniasis: re-examination of haematogenous disseminationTrans. R. Soc. Trop. Med. Hyg.Year: 199286439239410.1016/0035-9203(92)90233-31440813|
|89..||Marsden PD. Mucosal leishmaniasis (“espundia” Escomel, 1911)Trans. R. Soc. Trop. Med. Hyg.Year: 198680685987610.1016/0035-9203(86)90243-93037735|
|90..||de Magalhaes AV,Moraes MA,Raick AN,Llanos-Cuentas A,Costa JM,Cuba CC,Marsden PD. Histopathology of tegumentary leishmaniasis caused by Leishmania braziliensis braziliensis. 3. Cellular reactions in tissuesRev Inst Med Trop Sao PauloYear: 198628530031110.1590/S0036-466519860005000043589392|
|91..||Childs GE,Lightner LK,McKinney L,Groves MG,Price EE,Hendricks LD. Inbred mice as model hosts for cutaneous leishmaniasis. I. Resistance and susceptibility to infection with Leishmania braziliensis, L. mexicana, and L. aethiopicaAnn. Trop. Med. Parasitol.Year: 198478125346721612|
|92..||Sacks D,Anderson C. Re-examination of the immunosuppressive mechanisms mediating non-cure of Leishmania infection in miceImmunol. Rev.Year: 200420122523810.1111/j.0105-2896.2004.00185.x15361244|
|93..||Gumy A,Louis JA,Launois P. The murine model of infection with Leishmania major and its importance for the deciphering of mechanisms underlying differences in Th cell differentiation in mice from different genetic backgroundsInt. J. Parasitol.Year: 200434443344410.1016/j.ijpara.2003.11.02115013733|
|94..||Sacks D,Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in miceNat. Rev. Immunol.Year: 200221184585810.1038/nri93312415308|
|95..||Reis AB,Giunchetti RC,Carrillo E,Martins-Filho OA,Moreno J. Immunity to Leishmania and the rational search for vaccines against canine leishmaniasisTrends Parasitol.Year: 201026734134910.1016/j.pt.2010.04.00520488751|
|96..||Muller I,Kropf P,Etges RJ,Louis JA. Gamma interferon response in secondary Leishmania major infection: role of CD8+ T cellsInfect. Immun.Year: 1993619373037388359894|
|97..||Borges-Walmsley MI,Chen D,Shu X,Walmsley AR. The pathobiology of Paracoccidioides brasiliensisTrends Microbiol.Year: 2002102808710.1016/S0966-842X(01)02292-211827809|
|98..||Brummer E,Castaneda E,Restrepo A. Paracoccidioidomycosis: an updateClin. Microbiol. Rev.Year: 199362891178472249|
|99..||McEwen JG,Bedoya V,Patino MM,Salazar ME,Restrepo A. Experimental murine paracoccidiodomycosis induced by the inhalation of conidiaJ Med Vet MycolYear: 198725316517510.1080/026812187800002313612432|
|100..||Tobon AM,Agudelo CA,Osorio ML,Alvarez DL,Arango M,Cano LE,Restrepo A. Residual pulmonary abnormalities in adult patients with chronic paracoccidioidomycosis: prolonged follow-up after itraconazole therapyClin. Infect. Dis.Year: 200337789890410.1086/37753813130400|
|101..||Singer-Vermes LM,Caldeira CB,Burger E,Calich LG. Experimental murine paracoccidioidomycosis: relationship among the dissemination of the infection, humoral and cellular immune responsesClin. Exp. Immunol.Year: 1993941757910.1111/j.1365-2249.1993.tb05980.x8403521|
|102..||Mota NG,Rezkallah-Iwasso MT,Peracoli MT,Audi RC,Mendes RP,Marcondes J,Marques SA,Dillon NL,Franco MF. Correlation between cell-mediated immunity and clinical forms of paracoccidioidomycosisTrans. R. Soc. Trop. Med. Hyg.Year: 198579676577210.1016/0035-9203(85)90112-93832489|
|103..||Arango M,Yarzabal L. T-cell dysfunction and hyperimmunoglobulinemia E in paracoccidioidomycosisMycopathologiaYear: 198279211512310.1007/BF004680896982417|
|104..||Oliveira SJ,Mamoni RL,Musatti CC,Papaiordanou PM,Blotta MH. Cytokines and lymphocyte proliferation in juvenile and adult forms of paracoccidioidomycosis: comparison with infected and non-infected controlsMicrobes Infect.Year: 20024213914410.1016/S1286-4579(01)01521-011880044|
|105..||Benard G,Romano CC,Cacere CR,Juvenale M,Mendes-Giannini MJ,Duarte AJ. Imbalance of IL-2, IFN-gamma and IL-10 secretion in the immunosuppression associated with human paracoccidioidomycosisCytokineYear: 200113424825210.1006/cyto.2000.082411237434|
|106..||Karhawi AS,Colombo AL,Salomao R. Production of IFN-gamma is impaired in patients with paracoccidioidomycosis during active disease and is restored after clinical remissionMed. Mycol.Year: 200038322522910892991|
|107..||Kashino SS,Fazioli RA,Cafalli-Favati C,Meloni-Bruneri LH,Vaz CA,Burger E,Singer LM,Calich VL. Resistance to Paracoccidioides brasiliensis infection is linked to a preferential Th1 immune response, whereas susceptibility is associated with absence of IFN-gamma productionJ. Interferon Cytokine Res.Year: 2000201899710.1089/10799900031276610670655|
|108..||Calich VL,Kashino SS. Cytokines produced by susceptible and resistant mice in the course of Paracoccidioides brasiliensis infectionBraz. J. Med. Biol. ResYear: 199831561562310.1590/S0100-879X19980005000039698765|
|109..||Cano LE,Kashino SS,Arruda C,Andre D,Xidieh CF,Singer-Vermes LM,Vaz CA,Burger E,Calich VL. Protective role of gamma interferon in experimental pulmonary paracoccidioidomycosisInfect. Immun.Year: 19986628008069453644|
|110..||Souto JT,Figueiredo F,Furlanetto A,Pfeffer K,Rossi MA,Silva JS. Interferon-gamma and tumor necrosis factor-alpha determine resistance to Paracoccidioides brasiliensis infection in miceAm. J. Pathol.Year: 200015651811182010.1016/S0002-9440(10)65053-510793093|
|111..||Moreira, A.P., Dias-Melicio, L.A., Soares, A.M.: Interleukin-10 but not transforming growth factor beta inhibits murine activated macrophages Paracoccidioides brasiliensis killing: effect on H2O2 and NO production. Cell Immunol 263(2), 196–203. doi:10.1016/j.cellimm.2010.03.016|
|112..||Moreira AP,Dias-Melicio LA,Peracoli MT,Calvi SA,Victoriano de Campos Soares AM. Killing of Paracoccidioides brasiliensis yeast cells by IFN-gamma and TNF-alpha activated murine peritoneal macrophages: evidence of H(2)O (2) and NO effector mechanismsMycopathologiaYear: 20081661172310.1007/s11046-007-9046-318496766|
|113..||Gonzalez A,de Gregori W,Velez D,Restrepo A,Cano LE. Nitric oxide participation in the fungicidal mechanism of gamma interferon-activated murine macrophages against Paracoccidioides brasiliensis conidiaInfect. Immun.Year: 20006852546255210.1128/IAI.68.5.2546-2552.200010768942|
|114..||Ruas LP,Carvalho FC,Roque-Barreira MC. ArtinM offers new perspectives in the development of antifungal therapyFront. Microbiol.Year: 2012321810.3389/fmicb.2012.0021822715337|
|115..||Pot C,Apetoh L,Awasthi A,Kuchroo VK. Molecular pathways in the induction of interleukin-27-driven regulatory type 1 cellsJ. Interf. Cytokine Res. Off. J. Int. Soc. Interf. Cytokine Res.Year: 201030638138810.1089/jir.2010.0047|
|116..||Xu, M., Mizoguchi, I., Morishima, N., Chiba, Y., Mizuguchi, J., Yoshimoto, T.: Regulation of antitumor immune responses by the IL-12 family cytokines, IL-12, IL-23, and IL-27. Clin. Dev. Immunol. 2010 (2010). doi:10.1155/2010/832454|
|117..||Moreno AN,Jamur MC,Oliver C,Roque-Barreira MC. Mast cell degranulation induced by lectins: effect on neutrophil recruitmentInt. Arch. Allergy Immunol.Year: 2003132322123010.1159/00007430314646383|
|118..||Cardoso, M.R., Mota, C.M., Ribeiro, D.P., Santiago, F.M., Carvalho, J.V., Araujo, E.C., Silva, N.M., Mineo, T.W., Roque-Barreira, M.C., Mineo, J.R., Silva, D.A.: ArtinM, a d-mannose-binding lectin from Artocarpus integrifolia, plays a potent adjuvant and immunostimulatory role in immunization against Neospora caninum. Vaccine (2011). doi:10.1016/j.vaccine.2011.09.136|
|119..||Reis EA,Athanazio DA,Cavada BS,Teixeira EH,de Paulo Teixeira Pinto V,Carmo TM,Reis A,Trocolli G,Croda J,Harn D,Barral-Netto M,Reis MG. Potential immunomodulatory effects of plant lectins in Schistosoma mansoni infectionActa Trop.Year: 20081082–316016510.1016/j.actatropica.2008.05.02518579103|
|120..||Figueiredo JG,Bitencourt FS,Mota MR,Silvestre PP,Aguiar CN,Benevides RG,Nascimento KS,de Moura TR,Dal-Secco D,Assreuy AM,Cunha Fde Q,Vale MR,Cavada BS,Alencar NM. Pharmacological analysis of the neutrophil migration induced by D. rostrata lectin: involvement of cytokines and nitric oxideToxicon Off. J. Int. Soc. Toxinol.Year: 200954673674410.1016/j.toxicon.2009.05.037|
|121..||Lyu SY,Park WB. Mistletoe lectin transport by M-cells in follicle-associated epithelium (FAE) and IL-12 secretion in dendritic cells situated below FAE in vitroArch. Pharm. Res.Year: 20103391433144110.1007/s12272-010-0918-620945143|
|122..||Pelletier M,Lavastre V,Savoie A,Ratthe C,Saller R,Hostanska K,Girard D. Modulation of interleukin-15-induced human neutrophil responses by the plant lectin Viscum album agglutinin-IClin. Immunol.Year: 2001101222923610.1006/clim.2001.510511683582|
|123..||Hostanska K,Hajto T,Spagnoli GC,Fischer J,Lentzen H,Herrmann R. A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cellsNat. Immun.Year: 1995145–62953048933823|
|124..||Stanilova SA,Dobreva ZG,Slavov ES,Miteva LD. C3 binding glycoprotein from Cuscuta europea induced different cytokine profiles from human PBMC compared to other plant and bacterial immunomodulatorsInt. Immunopharmacol.Year: 20055472373410.1016/j.intimp.2004.12.00315710341|
|125..||Toledo KA,Scwartz C,Oliveira AF,Conrado MC,Bernardes ES,Fernandes LC,Roque-Barreira MC,Pereira-da-Silva G,Moreno AN. Neutrophil activation induced by ArtinM: release of inflammatory mediators and enhancement of effector functionsImmunol. Lett.Year: 20091231142010.1016/j.imlet.2009.01.00919428547|
|126..||Pereira-da-Silva G,Moreno AN,Marques F,Oliver C,Jamur MC,Panunto-Castelo A,Roque-Barreira MC. Neutrophil activation induced by the lectin KM+ involves binding to CXCR2Biochim. Biophys. ActaYear: 200617601869410.1016/j.bbagen.2005.09.01116260092|
|127..||Ganiko L,Martins AR,Freymuller E,Mortara RA,Roque-Barreira MC. Lectin KM+−induced neutrophil haptotaxis involves binding to lamininBiochim. Biophys. ActaYear: 200517211–315216310.1016/j.bbagen.2004.10.01215652190|
|128..||Ganiko L,Martins AR,Espreafico EM,Roque-Barreira MC. Neutrophil haptotaxis induced by the lectin KM+Glycoconj. J.Year: 199815552753010.1023/A:10069993230989881756|
|129..||de Almeida Buranello PA,Moulin MR,Souza DA,Jamur MC,Roque-Barreira MC,Oliver C. The lectin ArtinM induces recruitment of rat mast cells from the bone marrow to the peritoneal cavityPLoS OneYear: 201053e977610.1371/journal.pone.000977620339538|
|130..||Novak N,Yu CF,Bieber T,Allam JP. Toll-like receptor 7 agonists and skinDrug News Perspect.Year: 200821315816518560614|
|131..||Othoro C,Johnston D,Lee R,Soverow J,Bystryn JC,Nardin E. Enhanced immunogenicity of Plasmodium falciparum peptide vaccines using a topical adjuvant containing a potent synthetic Toll-like receptor 7 agonist, imiquimodInfect. Immun.Year: 200977273974810.1128/IAI.00974-0819047411|
|132..||Modabber F,Buffet PA,Torreele E,Milon G,Croft SL. Consultative meeting to develop a strategy for treatment of cutaneous leishmaniasis. Institute Pasteur, Paris. 13–15 June, 2006Kinetoplastid Biol. Dis.Year: 20076310.1186/1475-9292-6-317456237|
|133..||Arevalo I,Ward B,Miller R,Meng TC,Najar E,Alvarez E,Matlashewski G,Llanos-Cuentas A. Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulatorClin. Infect. Dis.Year: 200133111847185110.1086/32416111692295|
|134..||Agrawal S,Kandimalla ER. Synthetic agonists of Toll-like receptors 7, 8 and 9Biochem. Soc. Trans.Year: 200735Pt 61461146710.1042/BST035146118031246|
|135..||Raman VS,Bhatia A,Picone A,Whittle J,Bailor HR,O’Donnell J,Pattabhi S,Guderian JA,Mohamath R,Duthie MS,Reed SG. Applying TLR synergy in immunotherapy: implications in cutaneous leishmaniasisJ. Immunol.Year: 201018531701171010.4049/jimmunol.100023820601594|
|136..||Loures FV,Pina A,Felonato M,Calich VL. TLR2 is a negative regulator of Th17 cells and tissue pathology in a pulmonary model of fungal infectionJ. Immunol.Year: 200918321279129010.4049/jimmunol.080159919553529|
|137..||Custodio LA,Loyola W,Conchon-Costa I,da Silva Quirino GF,Felipe I. Protective effect of Artin M from extract of Artocarpus integrifolia seeds by Th1 and Th17 immune response on the course of infection by Candida albicansInt. Immunopharmacol.Year: 201111101510151510.1016/j.intimp.2011.05.00521609786|
[Figure ID: Fig1]
Three-dimensional structure of the ArtinM monomer. Motifs are distinguished by color, and the positions of the mannose-binding site and linker region are indicated. (Authorized reproduction from Rosa et al. )
[Figure ID: Figa]
[Figure ID: Fig2]
Immunological repercussions of ArtinM binding to antigen-presenting cells (APCs). The interaction of ArtinM with TLR2 N-glycans on APCs promotes IL-12 production. This cytokine induces increased IFN-γ production by natural killer (NK) and/or T cells, shaping a Th1 immune response. IFN-γ increases the microbicidal activity of macrophages. ArtinM stimulation of infected macrophages further increases the release of IL-12, constituting an amplification looping of Th1 immunity against intracellular pathogens
[Figure ID: Fig3]
ArtinM administration avoids the footpad lesion caused by L. major inoculation in BALB/c mice. Mice were administered with ArtinM (10 μg/mL) or vehicle (PBS) and infected (in the hind footpads) with 1 × 106 metacyclic promastigotes of L. major. The evolution of the lesion was assessed by measuring the footpad thickness, during an 8-week period. Modified of Panunto-Castelo et al. 
[Figure ID: Fig4]
Protective effect of ArtinM against P. brasiliensis infection. Untreated and ArtinM (10 μg/mL) treated BALB/c mice were intravenously infected with 1 × 106 virulent P. brasiliensis yeast cells. At the week 2 postinfection, the pulmonary tissue from untreated mice presented large granulomas surrounding a great number of yeast cells (a), while ArtinM treated mice showed small areas of mononuclear cells infiltration, in which few yeast cells were seen (b)
[Figure ID: Fig5]
Pleiotropic activity of ArtinM allows the construction of a Th1 immunity regulated by IL-10. ArtinM administration leads to the production of Th1 cytokines and IL-10, whereas no IL-4 is detected. The cell responding to ArtinM stimulus through IL-10 production has not yet been identified. IL-10 is assumed to counterbalance the inflammation associated with Th1 immunity, thereby preventing tissue injury
[Figure ID: Figb]
Some plant lectins that induce cytokines production
|ArtinM||Artocarpus heterophyllus||IL-12 and IL-10 (murine macrophages and dendritic cells)||[26, 74, 75]|
|TNF-α (murine mast cells)|||
|IL-10/IFN-γ (murine spleen cells)|||
|Banlec||Musa paradisiaca||IFN-γ, IL-10, and IL-4 (murine spleen cells)|||
|ConA||Canavalia ensiformis||IFN-γ (murine spleen cells)|||
|IFN-γ and IL-2 (murine spleen cells)|||
|IL-5, IL-10, TNF-α, and IFN-γ (human peripheral blood mononuclear cells—PBMCs)|||
|Conbr||Canavalia brasiliensis||IL-5, IL-10, TNF-α, and IFN-γ (human PBMCs)|||
|IFN-γ (murine spleen cells)|||
|Cramoll||Cratylia mollis||IFN-γ (murine spleen cells)|||
|DrosL||Dioclea rostrata||IL-5, IL-10, TNF-α, and IFN-γ (human PBMCs)|||
|TNF-α and IL1-β (peritoneal cavity of rat)|||
|Dviol||Dioclea violacea||IL-5 (human PBMCs)|||
|Dvirl||Dioclea virgata||IL-5, IL-10, TNF-α, and IFN-γ (human PBMCs)|||
|ASA-I||Alium sativum||IFN-γ and IL-12 (murine spleen cells)|||
|KML||Viscum album var. coloratum||IL-12 (human dendritic cells)|||
|ML-I||Viscum album||IL-12 (human PBMCs)|||
|IL-15 (human neutrophils)|||
|IL-6, TNF-α, and IL-10 (human PBMCs)|||
|PAA||Pisum arvense||IFN-γ (murine spleen cells)|||
|PHA||Phaseolus vulgaris||IFN-γ and IL-2 (murine spleen cells)|||
|PSA||Pisum sativum||IFN-γ and IL-2 (murine spleen cells)|||
|PWM||Phytolacca americana||TNF-α, IL-12, and IL-6 (human PBMCs)|||
|ScLL||Synadenium carinatum||IFN-γ and IL-10 (murine bronchoalveolar lavage fluid-BALF)|||
|UEA-1||Ulex europaeus||IL-2 and IFN-γ (mice spleen)|||
|WGA||Triticum vulgaris||IL-12 and IFN-γ (murine spleen cells)|||
ArtinM biological properties
|Cell type||Glycotarget||Triggered events||Final effect||Reference|
|Neutrophil||N-Glycans on CXCR2 (on the cell surface) and laminin (in the extracellular matrix)||(i) Signal transduction via G protein; (ii) tyrosine phosphorylation; (iii) increased TLR2 expression; (iv) release of leukotriene B4 and CXCL8; (v) shedding of L-selectin; (vi) superoxide production; (vii) phagocytic activity enhancement.||Cell activation and haptotaxis; enhancement of effector functions||[125, 126]|
|Mast cell||N-Glycans on Fcε receptor||(i) Cell degranulation; (ii) TNF-α release; (iii) mast cell recruitment from bone marrow||Cell recruitment and degranulation; contributes to neutrophil attraction||[117, 129]|
|Macrophage||N-Glycans on TLR2||(i) Signal transduction via MyD88; (ii) NF-kB activation; (iii) IL-12 production||Th1 immunity||[26, 31]|
|Dendritic cell||N-Glycans on TLR2||(i) Increased MHCII, CD80, and CD86 expression; (ii) IL-12 production||Cell maturation and Th1 immunity|||
Keywords: Keywords Plant lectins, ArtinM lectin, Immunomodulation, Toll-like receptor, Leishmania, Paracoccidioides brasiliensis.
Previous Document: Methane as an effective hydrogen source for single-layer graphene synthesis on Cu foil by plasma enh...
Next Document: Effects of Melatonin on Streptozotocin-Induced Retina Neuronal Apoptosis in High Blood Glucose Rat.